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タイトル: | Acute inhibition of AMPA receptors by perampanel reduces amyloid β-protein levels by suppressing β-cleavage of APP in Alzheimer's disease models |
著者: | Ueda, Sakiho ![]() ![]() ![]() Kuzuya, Akira ![]() ![]() Kawata, Masayoshi Okawa, Kohei Honjo, Chika Wada, Takafumi Matsumoto, Mizuki Goto, Kazuya ![]() ![]() ![]() Miyamoto, Masakazu Yonezawa, Atsushi Tanabe, Yasuto Ikeda, Akio ![]() ![]() ![]() Kinoshita, Ayae Takahashi, Ryosuke ![]() ![]() ![]() |
著者名の別形: | 上田, 紗希帆 葛谷, 聡 川田, 将義 本庄, 智香 和田, 隆史 松本, 瑞樹 後藤, 和也 宮本, 将和 米澤, 淳 田邉, 康人 池田, 昭夫 木下, 彩栄 髙橋, 良輔 |
キーワード: | Alzheimer's disease amyloid β-protein in vivo microdialysis perampanel β-Cleavage of APP |
発行日: | Nov-2023 |
出版者: | Wiley Federation of American Societies for Experimental Biology |
誌名: | The FASEB Journal |
巻: | 37 |
号: | 11 |
論文番号: | e23252 |
抄録: | Hippocampal hyperexcitability is a promising therapeutic target to prevent Aβ deposition in AD since enhanced neuronal activity promotes presynaptic Aβ production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aβ-evoked neuronal hyperexcitability, the acute effects of PER on Aβ metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aβ40 and Aβ42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aβ40 /Aβ42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP βCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPβ levels, a direct byproduct of β-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aβ-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aβ clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aβ, indicating that the acute effect of PER is predominantly on Aβ production. In conclusion, acute treatment of PER reduces Aβ production by suppressing β-cleavage of amyloid-β precursor protein effectively, indicating a potential effect of PER against Aβ pathology in AD. |
著作権等: | © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
URI: | http://hdl.handle.net/2433/287293 |
DOI(出版社版): | 10.1096/fj.202300837R |
PubMed ID: | 37850918 |
出現コレクション: | 学術雑誌掲載論文等 |
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